JP5436864B2 - Vx−950を含む共結晶体およびそれを含む医薬組成物 - Google Patents
Vx−950を含む共結晶体およびそれを含む医薬組成物 Download PDFInfo
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- JP5436864B2 JP5436864B2 JP2008557333A JP2008557333A JP5436864B2 JP 5436864 B2 JP5436864 B2 JP 5436864B2 JP 2008557333 A JP2008557333 A JP 2008557333A JP 2008557333 A JP2008557333 A JP 2008557333A JP 5436864 B2 JP5436864 B2 JP 5436864B2
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- cyclopropylamino
- carbonylamino
- cyclopenta
- hexahydro
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Description
本発明は、2006年2月27日出願の、米国仮特許出願番号第60/777221号の利益を主張しており、その全内容を出典明示により本明細書中に援用する。
C型肝炎ウイルス(“HCV”)による感染は、切実なヒトの医学的問題である。HCVは、非A型、非B型肝炎のほとんどの症例の原因因子として認識されており、全世界でヒト血清陽性率3%であると概算される[A. Alberti et al., “Natural History of Hepatitis C,” J. Hepatology, 31 (Suppl. 1), pp. 17−24 (1999)]。米国だけで400万人近くが、感染している可能性がある[M.J. Alter et al., “The Epidemiology of Viral hepatitis in the United States, ” Gastroenterol. Clin. North Am., 23, pp. 437−455 (1994); M. J. Alter “Hepatitis C Virus Infection in the United States,” J. Hepatology, 31 (Suppl. 1), pp. 88−91 (1999)]。
概して、本発明は、HCV阻害剤であるVX−950ならびに特定の共結晶形成剤(CCF)を含む組成物に関する。ある特定の条件下で、VX−950ならびにCCFは一体となって、結晶組成物、すなわち共結晶体を形成し得る。特定のVX−950共結晶体は、その遊離形と比較すると、アモルファス(amorphous)VX−950分散体よりも溶解性が改善され、水溶性が高く、固体状態の物理的安定性が高いために有利である。該特定のVX−950共結晶体はまた、アモルファス形態と比べて容積密度が高いので、投与剤形の質量が減少し、その結果、その丸剤負荷量が減少する。さらに、VX−950共結晶体は、スプレー乾燥、溶融押出、凍結乾燥または沈殿を必要とするアモルファス形態と比較して製造上の利点を提供する。
図1は、VX−950およびSAの共結晶体の熱重量分析(TGA)スペクトルを示す。
共結晶体の製造方法および特性化方法は、文献に詳しく記載される。例えば、Trask et al., Chem. Commun., 2004, 890−891;および、O. Almarsson and M.J. Zaworotko, Chem. Commun., 2004, 1889−1896を参照のこと。これらの方法は一般的に、本発明の共結晶体を製造および特性化するためにも適する。
サリチル酸(SA):70mgのVX−950およびCCFとして等モル当量のSA(Sigma Chemicals Co., St. Louis, MO, USA)を、50μLのメチルエチルケトン(“MEK”)と混合した。該成分をWig−L−Bug装置を用いて10分間ミル粉砕した。ミル処理後、バッチを真空オーブン中75度にて2時間乾燥させた。得られた物質は、オフホワイト色であった。
100mgのVX−950および等モル当量のサリチル酸、4−アミノサリチル酸およびシュウ酸(Sigma Chemicals Co., St. Louis, MO, USA)からなる群から選択されるCCFを、5分間ボルテックスにより混合した。この方法を2度行った。1度目は溶媒なしで行った。2度目は、4−アミノサリチル酸、サリチル酸およびシュウ酸それぞれに対して、100μLのアセトニトリル、メチルエチルケトン、および酢酸エチルを加えて行った。混合物を、蓋を閉めた反応ブロック(Radley Discovery Technologies, RR 98072)中に入れ、吸熱反応のため加熱した。混合物を吸熱温度で30分間放置し、その後、得られた混合物を蓋を開けて周囲条件下で冷却し、溶媒を用いたとき、それを除去した。
VX−950およびサリチル酸、4−アミノサリチル酸およびシュウ酸(Sigma Chemicals Co., St. Louis, MO, USA)からなる群から選択されるCCFを、50%トルエン/アセトニトリルの溶媒混合物中に別々に溶解した。溶解を、視覚的に透明な溶液が得られるまで回転および超音波処理して行った。VX−950溶液を、20mLのねじ式キャップ付きシンチレーションバイアル中で、全てについて最終容量3mLの0:1、1:3、1:1および3:1、1:0モル比でCCF溶液と混合した。これらのバイアルを、ドラフト中でキャップをはずし、溶媒を数日間かけて蒸発乾固させて固体物質を得た。
モデリングもまた、VX−950およびサリチル酸、4−アミノサリチル酸およびシュウ酸(Sigma Chemicals Co., St. Louis, MO, USA)からなる群から選択されるCCFの共結晶体が見られた。
各サンプルのTGAを、Model Q500 Thermogravimetric Analyzer (TA Instruments, New Castle, DE, USA)を、下記の構成要素:QAdv.exe version 2.2 build 248.0; RhDII.dII version 2.2 build 248.0; RhBase.dII version 2.2 build 248.0; RhComm.dII version 2.2 build 248.0; TaLicense.dII version 2.2 build 248.0;および、TGA.dII version 2.2 build 248.0と共に、そのThermal Advantage Q Series(商標)コントロールソフトウェア、Version 2.2.0.248, Thermal Advantage Release 4.2.1 (TA Instruments−Water LLC)を用いて行った。加えて、用いた分析ソフトウェアは、Universal Analysis 2000 software for Windows 2000/XP, version 4.1 D build 4.1.0.16 (TA Instruments)であった。
DSC分析を、MDSC Q100 Differential Scanning Calorimeter (TA Instruments)を、そのcontrol Thermal Advantage Q Series(商標)ソフトウェア, version 2.2.0.248, Thermal Advantage Release 4.2.1を下記の構成要素: QAdv.exe version 2.2 build 248.0; RhDII.dII version 2.2 build 248.0; RhBase.dII version 2.2 build 248.0; RhComm.dII version 2.2 build 248.0; TaLicense.dII version 2.2 build 248.0;および、DSC.dII version 2.2 build 248.0と共に用いて、行った。さらに、用いた分析ソフトウェアは、Windows 2000/ XP , version 4.1 D build 4.1.0.16用のUniversal Analysis 2000 ソフトウェアであった(TA Instruments)。装置をイリジウムで調整した。
XRPD分析において、BrukerまたはRigakuのどちらかの装置を用いた。
a.Bruker
XRPDパターンを、密閉チューブ源およびHi−Star 領域検出器を備えるBruker D8 Discover 回折計(Bruker AXS, Madison, WI, USA)を、室温にて、反射モードで用いることにより得た。銅標的X線チューブ(Siemens)を40kVおよび35mAで操作した。Brukerにより供されるグラファイトモノクロメータおよび0.5mmコリメーターを、平行な単色ビーム(CuKa、l=1.5418Å)を製造するために用いた。サンプルと検出器の間の距離は、約30cmであった。サンプルを、Si zero−background 薄板(The Gem Dugout, State College, PA)上に置き、その後、それをXYZ板上の中央に置いた。データを、Windows NT, version 4.1.16 用のGADDSソフトウェア(Bruker AXS, Madison, WI, USA)を用いて得た。2個のフレームを、フレーム当たり120秒の露光時間で記録した。サンプルは、露光中、XおよびY方向の両方に1mmの振幅で振動した。その後、データを0.02oの刻み幅の3oないし41o 2θの範囲で統合し、1つの連続したパターンにまとめた。Corundum plate (NIST standard 1976)を装置の調整に用いた。
XRPDパターンを、回転陽極RUH3R X線発生器(Rigaku, The Woodlands, TX, USA)およびRigaku Raxis IIC検出器を、室温にてトランスミッションモードで用いて記録した。50kVおよび100mAでのCuKの放射を用いた。集束ミラーおよびNiフィルターを用いて、平行な単色ビーム(l=1.5418Å)を製造した。該サンプルを、2mm直径のホウ素ガラスキャピラリー(Hampton Research, Aliso Viejo, CA, USA)中に入れ、実験中f軸の周囲を回転させた。サンプルと検出器の間の距離は、約25cmであった。Rigaku のCrystalclearソフトウェア, Version 1.3.5 SP2を用いて、300秒の露光時間で1つのフレームを記録した。その後、データを約0.02oの刻み幅の3oないし41o 2qの範囲で統合した。Silicon powder (NIST standard 640c)を装置の調整に用いた。
サンプルのアリコートをチューブ中に入れ、その後水性媒体を添加した。設定時間点において、上清のアリコートを回収し、0.45PTFEミクロンフィルター(Millex, LCR, Millipore)を通してろ過し、高速液体クロマトグラフィー(HPLC)分析(Agilent 1100; Palo Alto, CA, USA)を行った。該系は、25℃設定の自動サンプル器を備えていた。サンプル操作に関して、サンプルのアリコートをv/v比1:1でアセトニトリルを用いて希釈した。該サンプルを270nm設定の検出器でアイソクラクチック(isocratically)に流した。カラムは、XTerra(登録商標)フェニルカラム150mm×4.6mm、3.5μm粒子サイズ(P/N 186001144)(Waters, Milford, MA, USA)であった。移動層は、リン酸カリウム緩衝液(10mM、pH=7.0):メタノールの60:40(v/v)比であった。泳動を流速1mL/分で行い、15分以内に完了した。下記の表2に、人工腸液(pH6.8)中、室温にて24時間の時点でのVX−950および4−ASAの共結晶体の溶解度をまとめた(VX−950同等物と表される(VX−950は8.8分で溶出した))。
水性媒体中に懸濁した共結晶体の物理的安定性を評価した。該共結晶体粉末を、25℃にて、(1)非緩衝の脱イオン水、および(2)HPMCの1%(w/w)溶液(低粘性度)中に約6mg/mlの濃度でスラリーにした。該スラリーを、磁性撹拌棒およびプレートを用いて混合した。固体サンプルを、1、2、6および24時間の間隔でろ過により単離した。
本発明は、その詳細な説明と関連して記載されているが、上記の記載が説明を目的としており、本発明の範囲を限定せず、本発明の範囲は添付の特許請求の範囲により定義されることが、理解されるべきである。他の局面、利点および修飾は、添付の特許請求の範囲内である。
Claims (23)
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよびサリチル酸を含む共結晶体であって、X線粉末回折ピークを4.43、7.63、8.53、9.63、12.89、14.83、16.29 2θに有する、共結晶体。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよびサリチル酸のモル比が1:1である、請求項1記載の共結晶体。
- DSCサーモグラムにおけるピークを137℃および223℃にて有する、請求項2記載の共結晶体。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび4−アミノサリチル酸を含む共結晶体であって、X線粉末回折ピークを4.37、7.57、8.47、9.59、12.81および14.75 2θに有する、共結晶体。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび4−アミノサリチル酸のモル比が1:1である、請求項4記載の共結晶体。
- DSCサーモグラムにおけるDSCピークを177℃にて有する、請求項5記載の共結晶体。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよびシュウ酸を含む共結晶体であって、X線粉末回折ピークを4.65、6.17、8.21、9.63、12.65、14.91および28.97 2θにて有する、共結晶体。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよびシュウ酸のモル比が1:1である、請求項7記載の共結晶体。
- 式((1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミド)m:(CCF)n〔式中、CCFは、共結晶形成剤であるサリチル酸であり;mおよびnは、独立して1ないし5の整数である。〕で示される共結晶体であって、X線粉末回折ピークを4.43、7.63、8.53、9.63、12.89、14.83、16.29 2θに有する、共結晶体。
- 式((1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミド)m:(CCF)n〔式中、CCFは、共結晶形成剤である4−アミノサリチル酸であり;mおよびnは、独立して1ないし5の整数である。〕で示される共結晶体であって、X線粉末回折ピークを4.37、7.57、8.47、9.59、12.81および14.75 2θに有する、共結晶体。
- 式((1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミド)m:(CCF)n〔式中、CCFは、共結晶形成剤であるシュウ酸であり;mおよびnは、独立して1ないし5の整数である。〕で示される共結晶体であって、X線粉末回折ピークを4.65、6.17、8.21、9.63、12.65、14.91および28.97 2θにて有する、共結晶体。
- mおよびnが両方とも1である、請求項9〜11のいずれか1項に記載の共結晶体。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤であるサリチル酸の共結晶体を含む医薬組成物であって、共結晶体がX線粉末回折ピークを4.43、7.63、8.53、9.63、12.89、14.83、16.29 2θに有する、医薬組成物。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤である4−アミノサリチル酸の共結晶体を含む医薬組成物であって、共結晶体がX線粉末回折ピークを4.37、7.57、8.47、9.59、12.81および14.75 2θに有する、医薬組成物。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤であるシュウ酸の共結晶体を含む医薬組成物であって、共結晶体がX線粉末回折ピークを4.65、6.17、8.21、9.63、12.65、14.91および28.97 2θにて有する、医薬組成物。
- (1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤のモル比が1:1である、請求項13〜15のいずれか1項に記載の医薬組成物。
- 希釈剤、溶媒、賦形剤、担体または可溶化剤をさらに含む、請求項13〜15のいずれか1項に記載の医薬組成物。
- a.(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドを得る工程、
b.共結晶形成剤であるサリチル酸を得る工程、
c.固相中に共結晶体を形成するために、結晶化条件下、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドと共結晶形成剤を溶液中で粉砕、加熱、共昇華、共融解または接触させる工程(ここで、共結晶体はX線粉末回折ピークを4.43、7.63、8.53、9.63、12.89、14.83、16.29 2θに有する)、および
d.工程(c)で形成した共結晶体を単離する工程
を含む、共結晶体の製造方法。 - a.(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドを得る工程、
b.共結晶形成剤である4−アミノサリチル酸を得る工程、
c.固相中に共結晶体を形成するために、結晶化条件下、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドと共結晶形成剤を溶液中で粉砕、加熱、共昇華、共融解または接触させる工程(ここで、共結晶体はX線粉末回折ピークを4.37、7.57、8.47、9.59、12.81および14.75 2θに有する)、および
d.工程(c)で形成した共結晶体を単離する工程
を含む、共結晶体の製造方法。 - a.(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドを得る工程、
b.共結晶形成剤であるシュウ酸を得る工程、
c.固相中に共結晶体を形成するために、結晶化条件下、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドと共結晶形成剤を溶液中で粉砕、加熱、共昇華、共融解または接触させる工程(ここで、共結晶体はX線粉末回折ピークを4.65、6.17、8.21、9.63、12.65、14.91および28.97 2θにて有する)、および
d.工程(c)で形成した共結晶体を単離する工程
を含む、共結晶体の製造方法。 - 予め存在する共結晶体を種晶として共結晶体の製造に供する工程を含む共結晶体の製造方法であって、該予め存在する共結晶体は、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤であるサリチル酸を含み;該共結晶体は、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤であるサリチル酸を含み、共結晶体がX線粉末回折ピークを4.43、7.63、8.53、9.63、12.89、14.83、16.29 2θに有する、共結晶体の製造方法。
- 予め存在する共結晶体を種晶として共結晶体の製造に供する工程を含む共結晶体の製造方法であって、該予め存在する共結晶体は、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤である4−アミノサリチル酸を含み;該共結晶体は、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤である4−アミノサリチル酸を含み、共結晶体がX線粉末回折ピークを4.37、7.57、8.47、9.59、12.81および14.75 2θに有する、共結晶体の製造方法。
- 予め存在する共結晶体を種晶として共結晶体の製造に供する工程を含む共結晶体の製造方法であって、該予め存在する共結晶体は、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤であるシュウ酸を含み;該共結晶体は、(1S,3aR,6aS)−2−[(2S)−2−[[(2S)−2−シクロヘキシル−2−(ピラジン−2−カルボニルアミノ)アセチル]アミノ]−3,3−ジメチルブタノイル]−N−[(3S)−1−(シクロプロピルアミノ)−1,2−ジオキソヘキサン−3−イル]−3,3a,4,5,6,6a−ヘキサヒドロ−1H−シクロペンタ[c]ピロール−1−カルボキシアミドおよび共結晶形成剤であるシュウ酸を含み、共結晶体がX線粉末回折ピークを4.65、6.17、8.21、9.63、12.65、14.91および28.97 2θにて有する、共結晶体の製造方法。
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CA2643688A1 (en) | 2007-08-30 |
JP2009529006A (ja) | 2009-08-13 |
CN102614490A (zh) | 2012-08-01 |
EP1991229A2 (en) | 2008-11-19 |
JP2013234195A (ja) | 2013-11-21 |
WO2007098270A3 (en) | 2007-10-25 |
EP2340836A1 (en) | 2011-07-06 |
US20120088740A1 (en) | 2012-04-12 |
US8372846B2 (en) | 2013-02-12 |
US20070212683A1 (en) | 2007-09-13 |
WO2007098270A2 (en) | 2007-08-30 |
US8039475B2 (en) | 2011-10-18 |
AU2007217355A1 (en) | 2007-08-30 |
CN101489557B (zh) | 2013-12-18 |
AU2007217355B2 (en) | 2012-06-21 |
CN101489557A (zh) | 2009-07-22 |
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